Synovial rheumatoid factors (RF's) are qualitatively different from serum RF's in the same rheumatoid arthritis (RA) patients studied. For example, synovial 19S IgM RF has marked specificity for monomeric human IgG, and, in particular, for subclass IgG3. In contrast, autologous serum 19S IgM RF has greatest specificity for monomeric rabbit IgG and virtually none for human subclass IgG3. The synovium is central to the RA pathogenic process and, thus, RF produced in situ is more likely to represent pathogenic RF than is serum RF. This proposal will attempt to structurally define the antigenic determinant(s) on the IgG molecule against which synovial (presumably pathogenic) 19S IgM RF is directed in RA. In particular, 19S IgM RF specificity for and binding to enzymatically derived peptides from IgG3 (and possibly IgGl) will be examined in a RF plaque forming cell assay (RF-PFC) and by radioimmunoassay (RIA) using RF synthesized by Ra synovial cells. Amino acid sequencing of reactive peptides will be done to precisely characterize the antigenic determinant on the IgG molecule. The relationship between peptide structure and biologic activity will be determined by assessing the ability of closely related synthetic peptide analogs to bind with synovial 19S IgM RF (RIA) or to inhibit the synovial RF-PFC. Information generated from this proposal could provide critical new knowledge as to why and how the RA pathogenic process self-sustains itself. This in turn may allow the development of effective immunotherapeutic modalities (i.e., blocking or anti-idiotypic factors, etc) to treat this devastating disease.